Project Summary The focus of this work is on the modeling and analysis of the eye with regard to of the transport of drugs through the vitreous humor to the retina. With retinal diseases being one of the common causes of blind- ness amongst the elderly, it is imperative that efficient and effective drug-delivery methods targeting the retina be developed. To minimize drug distribution to undesired locations, intravitreal delivery, especially with the use of implants, has gained prominence. In this regard, a thorough understanding of the ocular transport processes is necessary, and a comprehensive mathematical model for the ocular fluid dynamics and transport phenomena with application to retinal drug delivery would be a major positive step. Among the challenges include understanding the transport of mac-romolecular and particulate drugs together with the effect of partial liquefaction (syneresis) of the vitreous with age. The specific aims include: 1. Mathematical Analysis and Measurement of Ocular Transport Parameters. In order utilize the mathematical model for real-life drug delivery, the biophyisical parameters relevant to fluid flow and drug transport need to be accurately determined for various drug types. These include, for example, the diffusion coefficient of the vitreouus humor, the permebility of the membranes around the vitreous, and the hindrance evaluation that large molecules and particles experience in the vitreous. We shall carry this out with the known scientific techniques, as well as the new methods that we have recently developed. 2. Ocular Fluid Dynamics and Transport: Comprehensive Mathematical Model with Syneresis. The measurements that will be made in Task 1 will be implemented in a mathematical model which entails the various transport processes of the physiologically natural fluids in the system as well the intervening drugs, coupled with permeation into the retinal region. The relevant transport equations will be solved computationally and validated with careful experimentation (Task 3). The model will be applied to provide drug delivery rates as a function of the location of drug deposition, drug type, the eye topography (degree of liquefaction and location) and other transport parameters of the eye. 3. Validate the Modeling and Analysis with Experiments. Applications of the mathematical model will be made for intravitreal delivery using sustained-release macrmolecular implants in animal models for which the requisite biophysical properties will have been determined in Task 1. Syneretic conditions will be created mechanically (avoiding chemicals) to different levels with a variety of possible eye topographies. This will be followed up with the determination of required delivery levels, based on drug type and delivery method. To overcome potential issues between our model and the experimental data, we will begin animal model experimentation early in the second year, along with the ex vivo experiments in order to modify and validate our model.